The present invention relates to a monoclonal antibody which binds to Folate receptor α (hereinafter, referred to as FOLR1) and exhibits antibody-dependent cellular cytotoxicity activity (hereinafter, referred to as ADCC activity) and/or complement-dependent cytotoxicity activity (hereinafter, referred to as CDC activity) or an antibody fragment thereof, a DNA encoding the antibody or the antibody fragment thereof, a vector comprising the DNA, a transformant obtained by introducing the vector, a method for preparing the antibody or the antibody fragment thereof using the transformant, and a therapeutic agent and a diagnostic agent comprising the antibody or the antibody fragment as an active ingredient.
FOLR1 is a GPI-anchored membrane protein having a high affinity for folate, and has an important functions relating to cell proliferation or survival (Non-Patent Literature 1). FOLR1 shows restricted-expression pattern in the normal tissues of the kidney, lung, intestine or the like (Non-Patent Literature 2).
The expression region is localized in the lumen. Meanwhile, FOLR1 expression in cancer tissues is not restricted to the lumen, and its high expression is observed in a variety of cancers such as ovarian cancer (Non-Patent Literature 2, Non-Patent Literature 3, Non-Patent Literature 4), renal cancer (Non-Patent Literature 2), lung cancer (Non-Patent Literature 2, Non-Patent Literature 3), breast cancer (Non-Patent Literature 2), mesothelioma (Non-Patent Literature 4).
In particular, it was reported that FOLR1 expression level is related to malignancy grade, progression, and prognosis in ovarian cancer (Non-Patent Literature 5, Non-Patent Literature 6). Furthermore, it was also reported that soluble FOLR1 was significantly elevated in the serum of ovarian cancer patients compared to the serum of healthy donors (Non-Patent Literature 7). Thus, FOLR1 is a promising target molecule for cancer treatment.
LK26 is known as a mouse monoclonal antibody against FOLR1 (Patent Literature 1). LK26 was humanized by CDR grafting to be administered to a patient as an antibody for cancer treatment (Patent Literature 2). However, its affinity was remarkably reduced by the humanization.
For this reason, Ebel et al. prepared MORAb-003 antibody which has equivalent affinity against FOLR1 to that of LK26 antibody, based on humanized LK26 antibody (Non-Patent Literature 8). It is considered that in vitro anti-tumor activity of MORAb-003 is attributed to ADCC activity and CDC activity.
On the other hand, there is a report that MORAb-003 has no inhibitory activity against binding of folate, 5-methyltetrahydrofolate (5-MTHF), or pemetrexed to FOLR1-positive cells, and the antibody alone has no inhibitory activity against proliferation of FOLR1-positive cells (Non-Patent Literature 9).
Phase I clinical trial reported that MORAb-003 showed safety and tolerability at administration doses from 12.5 to 400 mg/m2 (Non-Patent Literature 10). Moreover, Phase II clinical trial reported that MORAb-003 in combination with paclitaxel and carboplatin showed significant anti-tumor activity in patients with platinum-sensitive recurrent ovarian cancer.
However, clinical trial in patients with platinum-resistant recurrent ovarian cancer was discontinued because of the possibility of not meeting the endpoint of improving the predetermined statistical criteria (progression-free survival or overall survival duration) in an interim analysis.
An anti-cancer agent for targeting FOLR1 can be exemplified by EC-145 which is prepared by conjugating an anti-cancer agent to folate, in addition to the above anti-FOLR1 antibody. The folate-conjugated anti-cancer agent exhibits its efficacy, based on the folate-uptake property of FOLR1. Therefore, it is suggested that the folate-conjugated anti-cancer agent will be ineffective in the cancer cells with low folate uptake activity, although FOLR1 is expressed in the cancer cells of the body.
Despite continuous progress in the treatment of solid cancers and prognosis improvement, there has been no remarkable improvement in prognosis of ovarian cancer, since a therapy with a platinum agent emerged in 1980 (Non-Patent Literature 11), and ovarian cancer is still a main cause of cancer death in women. The reason is that ovarian cancer becomes resistant to the platinum agent and as a result, recurrent ovarian cancer is intractable.
That is, challenges in ovarian cancer treatment are to prolong a period before recurrence after response to the chemotherapy using a platinum agent or the like, to prevent resistance of ovarian cancer to the platinum agent, and to establish a therapy for platinum-resistant ovarian cancer.
Further, ovarian cancer is often associated with accumulation of ascitic fluid due to peritoneal dissemination. In particular, accumulation of ascitic fluid in the platinum-resistant ovarian cancer impairs QOL (Quality of Life), and thus there is a demand for therapeutic agents that are effective for cancer cells present in peritoneal dissemination or ascitic fluid as well as cancer cells in primary site.
There is also a demand for therapeutic agents effective for the cancer cells that show high FOLR1 expression but have low folate uptake activity.